How many of the molecular pieces that we use in medicinal chemistry are historical accidents? I’ve wondered this from time to time. There’s no doubt that drug structures are partly driven by ease of synthesis/commercial availability (these two go hand in hand), and these in turn are influenced by which reactions and feedstocks were exploited earlier. The Grignard reaction came well before palladium coupling methods, but there’s no reason that it had to, just to pick one example.
This new paper in J. Med. Chem. is what has me thinking about this again. The authors, from AstraZeneca, show that their in-house chemists tend to think of para-aromatic substituents more often than the other regioisomers, and that this preference is mirrored in the commercially available reagents (and indeed, in marketed drugs). The paper looks into sources of this bias – cost, the 1972 Topliss tree paper, and so on, but no single factor appears to be at work. What does seem to be going on is a self-reinforcing bias – there are more p-aromatics in the screening deck, so more of them hit. And there are more commercially available compounds with the structure, so more of them get made in turn.
We believe that ultimately the present day bias is now likely due to unjustified personal preferences and overused at the expense of meta and ortho regioisomers as well as other potentially diverse bioisosteres. This last point is an important conclusion. The bias for p-ClPh has propagated throughout the years and influenced design and synthesis plans. A simple extension into disubstituted aromatics revealed that chemists favor the similarly substituted compounds (e.g., diCl, diF, diMeO), with many of these having at least one element in the para position. This analysis also illustrated that many disubstituted compounds are underrepresented in the public domain, highlighting an opportunity for screening collection differentiation.
I suspect that there are many more such biases, based on availability of different heterocycles, lack of stereoselective methods in some areas, etc. Our screening collections (and our building block catalogs) are the work of human beings, making conscious and unconscious choices, not some random slice of chemical space.